1. Field of the Invention
The present invention relates to medical compositions and methods for the reparation of fibrotic lesional tissues and the prevention of fibrotic lesions, which compositions comprise one or more N-substituted 2(1-H) pyridones and/or one or more N-substituted 3(1H) pyridones as active anti-fibrotic ingredient(s).
2. Background Art
Herein, the term "anti-fibro", "anti-fibrotic" or "anti-fibrosis" refers to the reparations and/or prevention of pathological polymerization of collagen in lung fibrosis, arteriosclerosis, prostatic hypertrophy, keloid, myocarditis, collagen disease, scar, wrinkle, etc., and reparation as well normalization of the existing pathological fibrotic tissues.
Methods of preparation of some N-substituted 2(1-H) pyridones useful in the present invention are described in U.S. Pat. No. 3,839,346, issued Oct. 1, 1974, to Gadekar, and titled N-SUBSTITUTED PYRIDONE AND GENERAL METHOD FOR PREPARING PYRIDONES, the disclosure of which is incorporated by reference hereinto. That patent also describes use of those compounds in analgesic, anti-inflammatory, and anti-pyretic treatments. U.S. Pat. Nos. 3,974,281, issued Aug. 10, 1976; 4,042,699, issued Aug. 16, 1977; and 4,052,509, issued Oct. 4, 1977, all to Gadekar, describe further use of one of these compounds, 5-methyl-1-phenyl-2(1H) pyridone ("pirfenidone"), in lowering serum uric acid and glucose levels, treating upper respiratory inflammatory conditions, and treating inflammatory skin conditions, in humans and other mammals.
The use of pirfenidone in the reparation and prevention of fibrotic lesions is described in the above-referenced copending U.S. application Ser. No. 07/947,995, filed Sep. 21, 1992, U.S. Pat. No. 5,310,562 the disclosure of which is incorporated by reference hereinto.
It has been discovered by the present inventor that other N-substituted 2(1-H) pyridone compounds and/or N-substituted 3-(1H) pyridone(s) also have anti-fibrotic activity. Heretofore, before the discoveries of the inventions disclosed herein and in the above copending application, no effective pharmacological agent or composition has been available for the prevention or removal of pathologic fibrotic lesions of the lungs, prostate glands, musculoskeletal diseases, myocardial degeneration, myocardial infarction, arteriosclerosis, and other lesional fibroses.
For example, powerful anti-inflammatory glucocorticoids (hormones relating to carbohydrate metabolism) such as hydrocortisone or prednisolone administered in very large doses have repeatedly been shown to be ineffective against fibrotic disease. These glucocorticoids do not arrest or remove such life-threatening fibrotic lesions. The glucocorticoids may be effective, however, as anti-inflammatory agents under such condition that they may temporarily ameliorate the secondary acute inflammation flare-ups which intermittently occur in tissues or organs damaged by fibrotic disease. Indeed, excessive and prolonged administration of glucocorticoids in pulmonary fibrotic disease may cause destruction of tissues, due to fibrosis or an exacerbation and acceleration of the fibrotic destruction.
Antopol (1950) was the first of many investigators who found that the anti-inflammatory glucocorticoids readily enhance fibrotic degeneration of lung tissues. Similarly, the non-steroidal anti-inflammatory agents such as aspirin, salicylates, phenylbutazone, indomethacin, various phenylacetic acid derivatives, and the like have also failed to arrest formation of, or cause repair of progressive, chronic fibrotic damage to lung tissues, prostatic tissues, musculoskeletal tissues, etc.
Accordingly, it is a principal object of the present invention to provide compositions for the reparation and prevention of fibrotic lesional tissue.
It is an additional object of the invention to provide such compositions that comprise one or more N-substituted 2-(1H) pyridone(s) and/or N-substituted 3-(1H) pyridone(s) as active anti-fibrotic ingredient(s).
Other objects of the present invention, as well as particular features and advantages thereof, will be elucidated in, or be apparent from, the following description.